This announcement invites applications for establishment of the Gastroparesis Clinical Research Consortium (Consortium). Gastroparesis is a common condition of multiple different etiologies characterized by symptoms such as nausea, vomiting, bloating, abdominal pain and physiological abnormalities such as delayed gastric emptying. The consortium will consist of a network of clinical centers and one data-coordinating center, which will work cooperatively to conduct clinical research to elucidate the pathophysiology and develop better treatments for this condition.

The total amount to be awarded is $3 million per year for 5 years.

There will be approximately 4 to 6 clinical centers and one data coordinating center

This RFA will use the NIH cooperative agreement (U01) mechanism.

Eligible institutions include domestic for-profit or non-profit organizations, public or private institutions such as universities, colleges, hospitals, and laboratories, Units of State and local governments, eligible agencies of the Federal government.

Eligible individuals include employees of the above institutions who have the knowledge, skills and resources necessary to conduct clinical research in patients with gastroparesis.

Nature of research opportunity. The objective of this RFA is to invite applications to participate in a clinical research consortium in which individual clinical research centers, a data-coordinating center, and the NIH will work cooperatively to discover clinically relevant new information about this condition and improve treatment for patients.

Background information. Gastroparesis is a clinical syndrome characterized by multiple symptoms, including nausea, vomiting, bloating, abdominal pain, and early satiety. Physiological studies are characterized by delayed emptying of the stomach. There are multiple etiologies, such as diabetes and surgical injury to the vagus nerve, but the most common etiological category is idiopathic. The incidence and prevalence are not well defined in population-based studies, but the condition appears to be relatively common, affecting up to 5 million individuals in the United States. There is a marked reduction in quality of life, and in severe cases, the condition may be life threatening. Commonly used diagnostic tests in clinical practice are primarily limited to imaging of the GI tract and tests of emptying of a labeled meal; however, these tests have limited sensitivity and specificity. Many agents have been used in attempts to improve the symptoms of gastroparesis, such as antiemetic agents, prokinetic agents, botulinum toxin, pain therapies, and gastric pacemakers, but data from rigorous controlled trials is largely lacking.

Research progress in gastroparesis has been hampered by a number of hurdles. Studies to date have generally been conducted in single centers with a small number of subjects with one or only a few investigators. The limitations of small single center studies include referral bias in the patient population, limited range of clinical and research techniques available for study, and limited capacity to create resources, such as patient serum, DNA, tissue, and database repositories that could be used by other investigators.

Scientific knowledge to be achieved through research supported by this program. The program seeks to define patient characteristics, pathophysiological mechanisms, potential novel pathways for therapeutic intervention, and new diagnostic tests and treatments for patients with gastroparesis.

Objectives of research program. The overall objective of this research program is to conduct multicenter clinical research studies of patients with gastroparesis using defined clinical, diagnostic, and therapeutic interventions and to collect samples that may be useful for ancillary studies of etiology and pathogenesis. The intermediate and long-term objective is to improve the diagnosis and treatment of patients with gastroparesis.

Types of research and experimental approaches being sought. This announcement solicits applications from investigators who have access to patients with gastroparesis and who will suggest clinical research protocols that can be carried out by a multicenter consortium aimed at furthering the research objectives outlined above. Investigators may have expertise in clinical gastroenterology or gastrointestinal surgery, gastrointestinal physiology, gastrointestinal neuroendocrinology, gastrointestinal or brain imaging, pharmacology, or other disciplines that address the objectives of the study.

Examples of research topics. The research consortium will be expected to develop protocol studies that will further the objectives indicated above. While each applicant will propose studies in their individual applications, the final studies that are carried out by the consortium will be determined post-award through meetings of the steering committee of the consortium (see below). Examples of aims that are appropriate for the consortium include:

Identify the etiology of idiopathic gastroparesis, including environmental, genetic, and other risk factors.

Elucidate the mechanisms for dominant symptoms, such as nausea and vomiting.

Identify sensitive and specific diagnostic tests and protocols for gastroparesis that discriminate the condition from other diseases and predict response to different interventions, including EGG and novel imaging techniques.

Define the natural history of subgroups of patients with gastroparesis.

Define optimal medical, surgical, or other interventions to improve symptoms and outcomes, including gastric pacing.

Conduct pilot studies of novel pharmacological interventions.

Identify risk factors for progression or complications.

Refine quality of life measures specific for gastroparesis.

This announcement specifically is intended to support human research and is not intended to support studies of animal models of gastroparesis.

Project organization. This project will create a consortium of investigators who will carry out collaborative projects. The consortium will consist of approximately 4 to 6 clinical centers, one data coordinating center, and scientific staff of the NIDDK. Although each clinical center applicant will propose one or two studies for the consortium in their application, no study will be carried out until the consortium has met and the steering committee has approved studies to be carried out by the consortium. Thus, individual specific studies proposed in applications may not be carried out, but clinical center applicants nonetheless will be expected to participate in the conduct of studies agreed to by the consortium, including sharing of patient data, specimens and protocols as determined by the Steering Committee. The exact number and nature of protocols supported during the 5 year program will be determined by the Steering Committee, and the protocols will be subject to the availability of funds for the entire consortium. Each protocol will be implemented in a minimum of two of the clinical centers. The Steering Committee will be responsible for governance of the study and be composed of the Principal Investigator of each clinical center, the principal investigator of the data coordinating center, and the NIDDK Project Scientist. The Steering committee will establish subcommittees as needed. An independent Data and Safety Monitoring Board will be established by NIDDK to review protocols and monitor patient safety and performance of each study. The consortium will be expected to deposit appropriate biological specimens and data in the NIDDK Repository, which will be made available to all qualified investigators at a future date.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the U01 award mechanism(s). As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIDDK intends to support this research project for 5 years. There is no commitment to extend or reissue this opportunity at the end of 5 years at this time.

2. Funds Available

The NIDDK intends to commit approximately 3 million dollars in FY 05 to fund 4-6 clinical centers and one data coordinating center new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs up to $250,000 direct cost/year, $100,000 of which must be in the patient care category. The data coordinating center budget will be limited to no more than $750,000 direct cost/year. Future year costs will be distributed based on the recommended protocols, database development, or planning studies for future clinical trials. AWARDS MADE TO A PARTICULAR CENTER UNDER THIS RFA WILL DEPEND IN PART ON THE PROTOCOLS CARRIED OUT AND MAY BE MORE OR LESS THAN THE REQUESTED BUDGET.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Facilities and administrative costs are not included in the direct cost limitation, see NOT-OD-04-040.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

For-profit organizations

Public or private institutions, such as universities, colleges, hospitals, and laboratories

Units of State government

Units of local government

Eligible agencies of the Federal government

Domestic Institutions only

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

Individual institutions are limited to one clinical center and one data coordinating center application. If an individual institution submits both a clinical center and a data coordinating center application, two separate applications are required. Since the responsibilities of the clinical center and the data coordinating center are largely different and non-overlapping, it is expected that the two applications from a single institution would have largely or exclusively non-overlapping personnel. The data coordinating center must specifically include scientific expertise in gastroparesis, and to avoid duality of interest, that scientific expertise should be personnel who are not members of a clinical center.

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 11/2004). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

3. Submission Dates

Applications must be received on or before the receipt date described below (Section IV.3.A).

Prospective applicants are asked to submit a letter of intent that includes the following information:

Descriptive title of proposed research

Name, address, and telephone number of the Principal Investigator

Names of other key personnel

Participating institutions

Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date listed in the heading of this funding opportunity. If an application is received after that date, it will be returned to the applicant without review. Applications will be evaluated for completeness by CSR.

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK . Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

Applicants must describe plans to accommodate the stated program requirements, criteria, and staff involvement.

1. Clinical Center (CC) Applications

Each CC within the Consortium should propose a research plan that includes the structure of a large database as well as two clinical research protocols as models that could be used in the Consortium environment. Please note: the steering committee will make final decisions on the structure of the database and any clinical research protocols that are to be implemented. For development of a database, the application should address clinical definitions, nomenclature, terms, potential diagnostic criteria, demographic information, information from diagnostic tests and protocols that might be suitable, as well as potential data to be collected such as both routine and novel laboratory and physiological assessments, assessment of environmental or other risk factors, and quality of life measures. The above are examples, and not intended to be comprehensive or exclusive. The database should be constructed to address specific aims that are explicitly indicated.

The two specific clinical research protocols should demonstrate both knowledge of gastroparesis and innovative approaches to addressing specific aims. Each protocol should require sufficient subjects to necessitate the use of a Consortium with multi-center participation. Applicants should indicate knowledge of the number of patients required for each study based on sample size calculations. One protocol must be a short-term study (one year or less) and one a long-term study (one to three years). For the overall structure and factors that are included in the common database of patients include a justification for necessary information on patients to be included. For each of the two protocols include a description in approximately three pages of the rationale, research aims, outcome measures, and study design. In addition, provide a description of the proposed patient populations with an estimate of the expected distribution of male and female patients, ages.

The CC principal investigator should indicate for each protocol how many patients meeting proposed criteria are available in his/her CC and how many will be required from the entire Consortium (all of the CCs). In the discussion of outcome measures, it will be important to indicate appropriate objective measures of primary and secondary outcome. The CC principal investigators are encouraged to explore, within the context of their proposed protocols, new technologies to monitor disease progression and response to therapy. Funding for the relevant technology should be presently available for each protocol proposed. If relevant, it will also be important to include strategies to assure adherence to therapy as part of the protocol.

It is suggested that each protocol proposal be approximately three pages in length, including tables and figures. As noted below in the budget section, each clinical research protocol should include within the text (not on budget pages) estimates of the cost of the study, which may be used by the consortium steering committee for planning purposes.

To promote development of a collaborative program, the issues discussed below need to be addressed in each application for a CC within the Consortium. This material is in addition to the submission of research plans, as described above.

The following specific criteria should be addressed:

Qualifications and experience. Applicants for CCs must demonstrate experience and expertise to conduct clinical studies. This must include documentation of experience in the diagnosis and management.

Study population. CCs must demonstrate a history of evaluating and managing patients with gastroparesis. The CC should discuss the number of patients with gastroparesis seen and followed at the center in the previous five years that might have been eligible to enroll in the clinical database as well as in specific treatment, investigational or diagnostic protocols. Approximately half of the patients enrolled in the Consortium should be females. The applicant for a CC in the Consortium must include a description of patients seen with gastroparesis by sex, age categories, and ethnic/racial distribution, as well as recruitment source. Patient access may be developed by establishing links with other groups outside the CC's institution. If outside links are proposed, there must be a well described plan to link the individual CCs with community health care providers such as HMOs, clinics, or private practice physicians to ensure adequate numbers patients for clinical studies of therapeutic agents and management strategies. Applicants for a CC from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources are encouraged to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Project Coordinator or Principal Investigator should be included with the application.

Willingness to participate in the Consortium.

The principal investigator should state his/her general support of collaborative research and interaction with the NIDDK, the other CCs, and the DCC through the Consortium concept. Applicants should discuss their willingness, and that of the institutions involved, to pursue a per patient basis (capitation) of operational costs for each protocol. CCs must be able to interact with the DCC to transmit and edit data and should discuss their capability to participate in a distributed data entry system.

The CCs do not have to submit a Data and Safety Monitoring Plan (DSMP); however, they must state their willingness to follow the consortium DSMP that will be developed by the DCC in conjunction with the steering committee and approved by the NIDDK and the Data and Safety Monitoring Board.

Institutional resources for patient care and follow-up including personnel, space, and special laboratory facilities should be described.

2. Data Coordinating Center Applications (DCC)

A separate complete application is required from institutions applying to be the DCC for the Consortium. Applicants for the DCC component are not required to be a clinical site within the Consortium, though applicants for clinical sites may also submit a separate application to be the DCC, as noted above.

Applicants must describe plans to achieve the stated “Objectives and Scope,” ”Special Requirements,” and “Terms and Conditions of Award” stated in this RFA. In addition, applicants should document their willingness to participate on the Steering Committee and appropriate subcommittees, work cooperatively with other members of the Steering Committee, and follow the common protocol established cooperatively by the Steering Committee. Applicants must also address the following responsibilities of the DCC:

Participation in the design of the final protocol and development of the manual of operation, data collection forms, and questionnaires;

Development and implementation of systems for communication among Steering Committee members, and among study sites;

Filing of regulatory documents to the Food and Drug Administration including but not limited to, the Investigational New Drug application (IND), adverse event reporting, and IND annual reports;

Data collection, editing, processing, analysis, and reporting;

Monitoring of adherence to the protocol and of data quality; and

Establishment of procedures that insure the safety and confidentiality of all records including development of the DSMP for the consortium. Data management and quality control procedures must be detailed. Methods for assuring privacy and maintaining confidentiality should be included. Applicants must state their plans for the reporting of results that examine differences in treatment effects across these subgroups (see section, “Inclusion of Women and Minorities in “Research Involving Human Subjects”).

Applications may not exceed 25 pages for sections a - d, excluding appendices, which may contain copies of pertinent forms or examples of correspondence useful for coordinating tasks.

The following specific criteria should be addressed:

Qualifications and experience. The applicant for a DCC must demonstrate experience in the area of in coordinating multi-center clinical trials and epidemiological studies in all phases: protocol and manual of operations development, filing of FDA regulatory documents, staff training in study procedures, research instrument development, data collection and management, quality assurance, data analysis, distributed data entry, electronic communications, administrative management and coordination. Specific experience in coordinating or monitoring prior studies of gastrointestinal disease is not required, but the applicant should include relevant scientific expertise in gastroparesis in the application as a key collaborator and advisor. If the DCC application is from an institution also submitting a CC application, that collaborator should be different from the PI of the CC.

Study design and management. DCC proposals should discuss the applicant's familiarity and experience with various aspects of study design that would be important in developing clinical protocols, for example: eligibility criteria; baseline and outcome measures; methods of randomization; important considerations for making sample size and power calculations; methods and frequency of data collection and entry; monitoring accuracy of data collection; quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously; managing labeling and handling of serum and tissue samples (see below); and plans for statistical analysis. The DCC proposal should also describe their familiarity with model plans for managing the Data and Safety Monitoring Board and the Data and Safety Monitoring Plan.

The applicant for the DCC should delineate how laboratory specimens will be handled. NIDDK anticipates that some clinical outcome measures may be centrally assessed and that specimens will be centrally stored in the NIDDK repositories. Laboratories responsible to the DCC will manage specimens and laboratory studies as required by the Steering Committee. The costs of performing specific laboratory tests will be budgeted as a part of the per patient costs of each CC. The costs of specimen shipment as well as laboratory data acquisition and management will be a part of the budget of the DCC.

The applicant for the DCC must demonstrate sufficient scientific knowledge and expertise in gastroparesis in order to effectively interact with the clinical centers and their specific clinical research projects.

A limited, common amount of data will be collected on all patients at all sites. This database will include information on demographics, symptoms, standard laboratory and radiographic measures, complications, and other information that will be used by the network to determine etiology, natural history, and response to therapy and that will serve as a platform for conducting specific protocols. Within 3 pages, the DCC application must include a description and frequency of collection of core elements. Applicants should discuss the importance and potential difficulties in collecting such information. The DCC does not need to prepare the two research protocols required of clinical center applicants.

Budget and Related Issues:

Applicants should complete the budget information as directed in the PHS 398 application form.

1. Clinical Center Applications

Clinical centers (CC) should consider the following additional issues regarding budgets. The underlying concept of the Consortium is that a core effort is essential to maintain the infrastructure required to perform multiple clinical trials or clinical studies. Based on this approach, it is estimated that the individual CCs will require a minimum level of effort to sustain the organizational aspects of the Clinical Research Consortium. Therefore, individual CCs should submit requests for a CORE BUDGET. It is anticipated that this core budget will cover a minimum ten percent effort for the principal investigator, and a small percent effort for other key personnel (nurse, technician, clinic coordinator, secretary), and travel costs for two people (PI and one other key individual) to attend an average of four Consortium meetings per year in Bethesda, MD. These costs should be justified appropriately in the budget. This amount of the CORE BUDGET should not exceed $150,000/year direct cost.

In addition to the core budget, each clinical center will be provided funds for implementation of protocols. The precise number of protocols conducted will be determined by the Consortium Steering Committee and will depend on availability of funds. It is anticipated that after the first year, two to four protocols may be active each year. CCs should request PATIENT CARE costs in the amount of $100,000/year starting in the first year. This amount should be placed in the patient care category. The total direct cost budget should not exceed $250,000 ($150,000 for core budget and $100,000 patient care costs).

Note that ongoing annual budgets for protocols will be based on the protocols approved by the Consortium Steering Committee and will be funded through a per patient basis (capitation) funding mechanism. The individual CCs will be expected to project patient enrollment for a specific protocol during a specified time frame; continuation and level of funding for each CC will be based on actual recruitment and overall performance.

The Consortium awards will be subject to administrative review and adjustment annually.

2. Data Coordinating Center Applications

Applicants for the DCC should prepare budgets for five 12-month periods(not to exceed $750,000 direct cost per year) that roughly correspond with the standard coordinating center responsibilities outlined in other sections of this RFA. In the first year, DCC applicants should include all costs associated with the organization of all administrative aspects of the Consortium to be developed and with the initiation of one protocol to be developed and started. For subsequent years, applicants may assume that two to four protocols a year will be active, i.e. either in the protocol development, implementation, or analysis and writing phase. DCC should include costs for managing the Data and Safety Monitoring Board including the cost of meeting two times/year in Bethesda. Approximately $20,000/year should be budgeted for managing the Data and Safety Monitoring Board.

The DCC will be subject to administrative review annually. It is expected that all protocols will be performed in a manner consistent with United States Food and Drug Administration guidelines.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Investigators in the consortium will be expected to share protocols, critical reagents and data with other participating members of the consortium as an ongoing part of the collaborative studies.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Award Criteria.

Investigators in the consortium will be expected to share protocols, critical reagents and data with other participating members of the consortium as an ongoing part of the collaborative studies.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK . Incomplete applications will not be reviewed.

If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIDDK in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.

Receive a written critique.

Receive a second level of review by the National Institute of Diabetes and Digestive and Kidney Diseases Advisory Council.

3. Merit Review Criteria

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

2. Approach. Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

3. Innovation. Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

4. Investigators. Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

3.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

3.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

3.C. Sharing Research Data

1. Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The funding organization will be responsible for monitoring the data sharing policy, http://grants.nih.gov/grants/policy/data_sharing. The reviewers will not be asked to evaluate the adequacy of the proposed plan to share data. A data sharing plan will be developed by the DCC, but all applicants (CC and DCC) must acknowledge in a "Sharing Plan" in the proposal that they will share the specimens and data collected with the wider scientific community through eventual transfer of these materials to the NIDDK Central Biosample and Data Repositories or through another mechanism determined by NIDDK.

Reviewers will not be asked to evaluate the adequacy of the plan to share resources. Program staff will be responsible for the administrative review of the plan for sharing research resources. Investigators in the consortium will be expected to share protocols, critical reagents and data with other participating members of the consortium as a ongoing part of the collaborative studies. A data sharing plan will be developed by the DCC, but all applicants (CC and DCC) must acknowledge in a "Sharing Plan" in the proposal that they will share the specimens and data collected with the wider scientific community through eventual transfer of these materials to the NIDDK Central Biosample and Data Repositories or through another mechanism determined by NIDDK.

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the applicant organization by email. The NGA signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (U O1 ), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined above.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for:

1. Research design and protocol development, including definition of objectives and approaches, planning, implementation, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.

2. Establishing a Steering Committee to coordinate and manage the project. Awardee(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.

3. Designating Protocol Chairs. The Principal Investigators (for studies involving multiple coordinated awards) shall designate a single Protocol Chairperson (if the Principal Investigator does not assume this role) for each protocol within the described research plan. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Any significant modifications to approved protocols must be submitted to the Steering Committee by the Protocol Chairperson.

4. Implementing the core data collection method and strategy collectively decided upon by the Steering Committee. For a study involving multiple institutions, it is the responsibility of each awardee/site to ensure that data will be submitted in a timely way to the central Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.

5. Establishing mechanisms for quality control and monitoring. Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple awards, strategies for the analyses of pooled data will be developed by the Steering Committee.

6. Submitting interim progress reports, when requested, to the NIDDK Program Director including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the Steering Committee may require additional information from individual awardees/sites. Such reports are in addition to the annual awardee noncompeting continuation progress report.

7. Establishing procedures, where applicable, for all participating institutions in coordinated awards to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects, and the NIH policy requirements for the inclusion of women, minorities and children.

8. Cooperating in the reporting of the study findings. The awardee(s) will retain custody of and have primary rights to the data developed under these awards, subject to the Government rights of access consistent with current HHS, PHS and NIH policies. The NIDDK will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NIDDK of pooled data and conclusions, are to be developed by the Principal Investigator or Steering Committee, as applicable. NIH policies governing possible co-authorship of publications with NIDDK staff will apply in all cases. In general, to warrant co-authorship, NIDDK staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts.

9. Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of study resources or citing the name of the study or NIDDK support; or special access to study results, data, findings, or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIDDK.

10. Study investigators are encouraged to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and governances.

11. The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archival and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. The Data Coordinating Center (DCC) will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, processing, receipt, and storage of study samples that are to be maintained in the Repository. In addition, the DCC will coordinate with the NIDDK Data Repository to prepare the collected data for eventual archiving and distribution. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study's Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing ( http://grants.nih.gov/grants/policy/data_sharing/ and, http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm) through a process that will include prioritized distribution based on review of the scientific merit of the proposed use. Therefore, it is expected that samples and data collected will be available to the broader scientific community, after a proprietary period, at no charge other than the cost of reproduction and distribution.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

An NIDDK Project Scientist will have substantial involvement in the project above and beyond normal stewardship and monitoring of the award, as described below.

1. Being the contact point for all facets of the scientific interaction with the awardee (s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIDDK staff to provide advice to the awardee on specific scientific and/or analytic issues. Such staff may include another Project Scientist, Scientific Advisors or Analyst, who will provide direct technical assistance to the awardees to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.

2. For multi-institutional protocols, convening the first meeting of and subsequent participation in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or designee will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.

3. Serving as a resource with respect to other ongoing NIDDK activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort.

4. Substantial involvement assisting in the design and coordination of research activities for awardees as elaborated below:

a. Assisting by providing advice in the management and technical performance of the investigations, coordinating clearances for investigational agents held by NIDDK. The NIDDK may reserve the right to cross file or independently file an Investigational New Drug Application form with the FDA.

b. For multi-institutional protocols, through participation in the Steering Committee and with the agreement of the Principal Investigator(s) of any coordinating center and data management centers, the NDDK Project Scientist or designee may coordinate activities among awardees by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and in the publication of results.

c. Reviewing and approving advice regarding the establishment of mechanisms for quality control and study monitoring.

An NIDDK Program Director identified in the Notice of Grant Award will be responsible for the normal stewardship and monitoring of the award. The Program Director may also serve as the Project Scientist.

The NIDDK Program Director responsibilities include:

1. Retaining overall programmatic responsibility for the award, and will clearly specify to the awardee the name(s) and role (s) of any additional individuals with substantial involvement in the project and the lines of reporting authority.

2. Interacting with the principal investigator( s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the principal investigator and staff, periodic site visits for discussions with awardee research teams, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee, data safety and monitoring board, and related meetings. The NIDDK retains, as an option, periodic external review of progress.

3. Reviewing and approving protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. The NIDDK Program Director will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure (except for patients already on-study).

4. Making recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.

2.A.3. Collaborative Responsibilities

In addition to the interactions defined above, NIDDK Staff and Awardees shall share responsibility for the following activities:

1. Steering Committee.

A Steering Committee organized by the NIDDK Program Director will be the main oversight body of the study. The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols, approve the common protocols, facilitate the conduct of participant follow-up, monitor completeness of data collection and timely transmission of data to the DCC, and report various study results. It will also be responsible for establishing study policies in such areas as access to patient data, publications and presentations, and performance standards. Major scientific decisions regarding the core data will be determined by the Steering Committee.

The Steering Committee will be composed of all Principal Investigators (data coordinating center and clinical centers), the NIDDK Project Scientist and others from the DCC, the clinical sites and the NIDDK as deemed necessary; however, only the principal investigators and the NIDDK Project Scientist or designee will be voting members.

A Chairperson for the steering committee will be selected by the NIDDK program director from among the principal investigators. The Chairperson is responsible for coordinating the Committee activities, for preparing meeting agendas, and for scheduling and chairing meetings.

2. Data Safety and Monitoring Board.

An independent Data and Safety Monitoring Board will be established by the NIDDK. The Data and Safety Monitoring Board will review interim results periodically as established in the data and safety monitoring plan and report to the NIDDK program director. The NIDDK Program Director will report in writing to the Steering Committee on the recommendations of the DSMB and the NIDDK concurrence/non-concurrence of the DSMB recommendations. The principal investigators will assume responsibility for reporting of the DSMB and the NIDDK recommendations to their respective Institutional Review Boards.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Award Criteria

The following will be considered in making funding decisions:

Scientific merit of the proposed project as determined by peer review

Availability of funds

Relevance of program priorities

NIDDK will also consider the following additional criteria in making funding decisions:

Evidence presented indicating the potential of the applicant to participate in a cooperative multicenter research study

Evidence that the applicant has access to a suitable number of research subjects that may be required by the overall consortium, or access to specific subpopulations of patients

Potential for proposed studies to be implemented in multiple clinical centers of the consortium

Potential for applicant institution to provide scientific expertise that will complement the final composition of investigators participating in the consortium

Institutional research resources available, such as the presence of an NIH funded General Clinical Research Center

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

Public Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.